Synthesis of N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl} amine

Article abstract of DOI:10.1021/jo0349633

N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl} amine (1)¹ is a key intermediate in the preparation of premafloxacin (2), which was under development as an antibiotic for use against pathogens of veterinary importance. This paper describes the development of a practical, efficient, and stereoselective process for the preparation of 1 from isobutyl (3S)-3-{methyl[(1S)-1-phenylethyl]-amino}butanoate (5c). The key steps in the synthetic sequence are an asymmetric Michael addition, which yields 5c, and a stereoselective alkylation, which yields (3S,4S)-3-allyl-1,4-dimethylazetidin-2-one (17).

Full text of DOI:10.1021/jo0349633

Syn th esis of N-Meth yl-N-{(1S)-1-[(3R)-p yr r olid in -3-yl]eth yl}a m in e†
Thomas J . Fleck,‡ William W. McWhorter, J r.,*,§ Richard N. DeKam,‡ and
Bruce A. Pearlman
Early Process Research and Development, Medicinal Chemistry Research, and Chemical Research and
Development, Pfizer, Inc., Kalamazoo, Michigan 49001
will.mcwhorter@worldnet.att.net
Received J uly 3, 2003
N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl}amine (1)1 is a key intermediate in the preparation
of premafloxacin (2), which was under development as an antibiotic for use against pathogens of
veterinary importance. This paper describes the development of a practical, efficient, and
stereoselective process for the preparation of 1 from isobutyl (3S)-3-{methyl[(1S)-1-phenylethyl]-
amino}butanoate (5c). The key steps in the synthetic sequence are an asymmetric Michael addition,
which yields 5c, and a stereoselective alkylation, which yields (3S,4S)-3-allyl-1,4-dimethylazetidin-
2-one (17).
SCHEME 1
N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl}amine
(1)1 is a key intermediate in the preparation of prema-
floxacin (2), which was under development as an anti-
biotic for use against pathogens of veterinary importance.
Since the three stereoisomers of premafloxacin are much
less active than premafloxacin itself, the development of
a practical, efficient, stereoselective synthesis of the
intermediate diamine 1 was of crucial importance.
pared from the readily available (S)-(-)-R-methyl-
benzylamine. The chiral center at C.3 of 1 is then set
relative to the previously prepared asymmetric center by
using the chelation-controlled alkylation of â-aminobu-
tanoates developed by Seebach and co-workers.3 The use
of allyl bromide as the alkylating agent should lead to 6.
We envisioned that the double bond of the allyl group
could be cleaved oxidatively and the resulting aldehyde
or alcohol could in turn be converted to an amine. A
variety of methods for this transformation are available.
This amine should readily cyclize to a γ-lactam, reduction
of which results in the formation of 1.
We prepared (S)-â-aminobutanoates using the asym-
metric Michael addition as shown in Scheme 2. Davies
and Ichihara2b reacted tert-butyl crotonate with the
lithium amide prepared from (S)-(N-benzyl)[N-(1-phenyl)-
ethyl]amine4 at -78 °C in THF to obtain a diastereo-
merically pure product in high yield. We found that this
reaction also occurred with complete diastereoselectivity
at -40 °C. We investigated the addition of the same
In this paper, we will describe the evolution of a
method for the preparation of N-methyl-N-{(1S)-1-[(3R)-
pyrrolidin-3-yl]ethyl}amine (1) into a highly efficient and
stereoselective process. Our initial plan for the synthesis
of 1 is shown in Scheme 1. We realized that the stereo-
chemistry at the center that becomes C.1′ of 1 could be
fixed in an absolute sense by means of an asymmetric
Michael reaction.2 The chiral lithium amide 4-Li (R′ )
Bn)2b has been shown to add to crotonate esters 3 to yield
optically active â-aminobutyrates 5 with very high de-
grees of diastereoselectivity.2 The chiral template, (S)-
(N-benzyl)[N-(1-phenyl)ethyl]amine, can easily be pre-
* Address correspondence to this author. Phone: (269) 385-3003.
† This paper is dedicated to the memory of our colleague and friend,
Tom Fleck, who passed away March 4, 2003.
‡ Early Process Research and Development.
§ Medicinal Chemistry Research.
Chemical Research and Development.
(1) Plummer, J . S.; Emery, L. A.; Stier, M. A.; Suto, M. A.
Tetrahedron Lett. 1993, 34, 7529-7532.
(2) (a) Hawkins, J . M.; Fu, G. C. J . Org. Chem. 1986, 51, 2820-
2822. (b) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,
183-186. (c) Hawkins, J . M.; Lewis, T. A. J . Org. Chem. 1992, 57,
2114-2121. (d) Costello, J . F.; Davies, S. G.; Ichihara, O. Tetrehedron:
Asymmetry 1994, 5, 1999-2008.
(3) (a) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28,
3103-3106. (b) Estermann, H.; Seebach D. Helv. Chim. Acta 1988,
71, 1824-1839.
(4) Davis, F. A.; McCauley, J . P., J r.; Chattopadhyay, S.; Harakal,
M. E.; Towson, J . C.; Watson, W. H.; Tavanaiepour, I. J . Am. Chem.
Soc. 1987, 109, 3370-3377.
10.1021/jo0349633 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/19/2003
9612
J . Org. Chem. 2003, 68, 9612-9617

N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl}amine
SCHEME 2a
Michael reaction as shown in Scheme 2. Hydrogenolytic
cleavage of the two benzyl groups of the ethyl or tert-
butyl â-aminobutanoate (5a or 5b) at 30 psi of hydrogen
in the presence of Pearlman’s catalyst7 cleanly yielded
ethyl or tert-butyl (S)-â-aminobutanoate (7a or 7b). The
crude methanol solution of the â-aminobutanoate (7a or
7b) was treated with benzyl chloroformate in a two-phase
mixture of 1 M KHCO3 and ethyl acetate to yield the
benzyl carbamate (Cbz) derivative of the methyl or tert-
butyl (S)-â-aminobutanoate (8a or 8c) in high overall
yield.8 Ester exchange from an ethyl to a methyl ester
takes place under these reaction conditions, but trans-
esterification was not observed with the tert-butyl ester.
Although distillation of the ethyl or tert-butyl (S)-â-
aminobutyrate (7a or 7b) can be carried out, this is not
necessary prior to reprotection as the Cbz derivative.
Alkylation of the methyl or tert-butyl â-aminobu-
tanoate 8a or 8c with allyl bromide according to the
conditions of Seebach and Estermann yielded the corre-
sponding R-allyl ester.3 The diastereoselectivity was
>91%.9 Estermann and Seebach report a diastereoselec-
tivity of 97% for the alkylation with allyl bromide of the
very closely related methyl â-[(N-benzoyl)amino]butyrate.
The methyl R-allyl-â-aminobutanoate 6a was subjected
to ozonolysis followed by reductive workup with dimethyl
sulfide and the resulting mixture of cleavage products
was reductively aminated with benzylamine and subse-
quently cyclized to pyrrolidinone 9. Sodium cyanoboro-
hydride was superior to sodium borohydride and sodium
triacetoxyborohydride for this reductive amination. The
methyl and ethyl R-allyl-â-aminobutanoates can be used
in this ozonolysis/reductive amination reaction sequence;
however, the γ-lactam cyclization product could not be
detected when the corresponding tert-butyl ester was
employed in this reaction sequence.
Pyrrolidinone 9 was reduced with lithium aluminum
hydride in refluxing THF to yield pyrrolidine 10. Hydro-
genolysis of the benzyl group with Pearlman’s catalyst
under 30 psi of hydrogen yielded the target pyrrolidine
1 as a clear, volatile oil. The overall yield of benzyl
pyrrolidine 10 from ethyl crotonate was 23% for seven
steps.
To streamline the synthetic sequence, we sought to
eliminate the need for the steps in which protecting
groups are exchanged and to directly introduce the
N-methyl group of 1 from the initial stages of the
synthetic sequence. As shown in Table 1 and Scheme 3,
we examined the addition of lithium amides derived from
the sterically less demanding (S)-(N-methyl)[N-(1-phen-
yl)ethyl]amine10,11 4b to a series of crotonate esters. This
amine also showed a very high degree of diastereoselec-
tivity (18:1) in the asymmetric Michael addition at
a
Reagents and conditions: (a) Pd(OH)2/C, 30 psi H2, MeOH;
(b) BnOCOCl, 1 M aq KHCO3, EtOAc, MeOH (89% for a and b for
the preparation of 8a ); (c) p-TsOH, EtOH; (d) LDA, allyl bromide,
THF, -75 °C (77% when R ) Me); (e) O3, MeOH, -78 °C; (f) Me2S;
(g) BnNH2, HOAc, NaCNBH3, THF, MeOH (59% for e, f, and g
when R ) Me); (h) LAH, THF, reflux (85%); (i) Pd(OH)2/C, 30 psi
H2, MeOH.
chiral lithium amide to ethyl crotonate because the tert-
butyl ester did not participate in a subsequent reaction
(vide infra). When ethyl crotonate was reacted with the
chiral lithium amide in THF at -78 °C, the Michael
adduct was obtained in 68% yield with a diastereoselec-
tivity of 34:1.5 Unlike the reactions with tert-butyl
crotonate, a minor byproduct, a diastereomeric mixture
of â-aminoamides,6 resulted from attack of excess chiral
lithium amide on the ethyl ester group of either the
Michael adduct or the crotonate ester.
We synthesized the target pyrrolidine 1 from the di-
N-benzyl-â-aminobutanoate products (5a and 5b) of the
(5) The ratio was judged by peak heights in the NMR of the signals
for the methylene protons R to the carbonyl of the ethyl ester in the
two diastereomers.
(6) The following mass spectral data were obtained for the byproduct
21: 491 (M+ + H, rel intensity 52%); 399 (22); 385 (48); 281 (19); 238
(45); 210 (16); 105 (86); 91 (100). Integration of the signals for the
methylene protons R to the carbonyl of the amide in the 300-MHz 1H
NMR indicated a 3.5:1 ratio of diastereomers.
(7) Furukawa, M.; Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem.
Pharm. Bull. J pn. 1979, 27, 2223-2226.
(8) Schmidlin, T.; Burckhardt, P. E.; Waespe-Sarcevic, N.; Tamm,
C. Helv. Chim. Acta 1983, 66, 450-465.
(9) The ratio was judged by peak heights in the NMR of the signals
for the C-2′ methyl group in methyl (2S)-2-((1S)-1-{[(benzyloxy)-
carbonyl]amino}ethyl)pent-4-enoate and its diastereomer.
(10) (S)-(N-Methyl)[N-(1-phenyl)ethyl]amine (4b) was prepared from
N-formyl-N-(S)-methylbenzylamine (4c), which was in turn prepared
from (S)-methylbenzylamine.
(11) After our initial disclosure of the use of this reagent in
asymmetric Michael additions [WO 9426708 1994], Davies’ group
disclosed its use: Davies, S. G.; Smyth, GD. Tetrahedron: Asymmetry
1996, 7, 1001-1004.
J . Org. Chem, Vol. 68, No. 25, 2003 9613

Fleck et al.
TABLE 1. Asym m etr ic Mich a el Ad d ition s
reaction
temp, °C
yield of
5, epi-5, %
yield of
byproduct 11, %
R
R′
diastereoselectivitya
t-Bu
Et
Me
Et
i-Bu
i-Bu
i-Bu
neo-Penb
Bn
Bn
-78
95, -
68, 2
73, 4
84, 5
88, 5
83, 5
78, 7
49, 12
one isomer detected
0
-78
34:1
18:1
17:1
18:1
17:1
11:1
4:1
minor product
Me
Me
Me
Me
Me
Me
-70
-70
23
11
7
12
15
39
-70 (0.2 M)
-70 (0.6 M)
-40
-70
a
Ratio determined by comparing the peak heights of corresponding signals in the 1H NMR spectra of the crude reaction products.
b
Inverse addition.
SCHEME 3
SCHEME 4a
-70 °C. The degree of diastereoselectivity was main-
tained independent of the steric bulk of the ester alkyl
group. The increasing bulk of the ester alkyl group did,
however, minimize the formation of the amide byprod-
ucts. The level of amide byproduct is 7%, 11%, and 23%
for isobutyl crotonate, ethyl crotonate, and methyl cro-
tonate, respectively. These studies revealed that the
reaction of isobutyl crotonate with the sterically less
demanding lithium amide maximized the diastereose-
lectivity of the â-aminobutanoate formation and, at the
same time, minimized the formation of byproduct amide
11.12 The diastereomer and byproduct amide could be
completely removed by recrystallization to yield pure 5c
(5, where R ) i-Bu and R′ ) Me).
a
Reagents and conditions: (a) n-BuLi (1 equiv), THF, -78 °C;
(b) methyl crotonate, -78 °C; (c) allyl bromide (2 equiv), 0 °C (75-
80% for a, b, and c); (d) O3, MeOH; (e) Me2S; (f) BnNH2, THF,
MeOH; (g) AcOH, NaBH4; (h) LAH, THF; (i) Pd(OH)2/C, H2, EtOH.
In an attempt to further streamline the synthesis of
1, we examined the direct alkylation of the anion, which
results from the addition of the lithium amide to the
crotonate ester. In this way, we hoped to introduce the
correct stereochemistry of the two chiral centers of 1 in
one step. The anion, which resulted from addition of the
chiral lithium amide of 4b to methyl crotonate, was
directly treated with allyl bromide in a one-pot procedure.
This resulted in an inseparable mixture of products 12
in a 3:1 ratio in 75-80% yield. This mixture of isomers
12 was subjected to ozonolytic cleavage of the double bond
to yield a diastereomeric mixture of aldehydes 13 after
reductive workup with dimethyl sulfide. The mixture of
isomers 13 was treated with benzylamine and the
intermediate imine was directly reduced with sodium
borohydride to yield 14, which cyclized in situ to an
isomeric mixture of lactams 15. The diastereomers 15
could be chromatographically separated. The pyrrolidine
that resulted from the major diastereomer was not 1, but
its diastereomer 1a . Thus, the major isomer of the
mixture of 12, obtained from the tandem Michael addi-
tion-alkylation sequence, apparently had the syn ster-
eochemistry. Davies and co-workers have demonstrated
that there is a general, but modest tendency for the anti
stereochemistry to predominate over the syn stereochem-
istry in closely related tandem Michael addition-alky-
lation reactions.13 Epimerization at the center R to the
methyl ester during the conversion of 12 to 1a could
explain this discrepancy; however, we did not observe
epimerization at this center during the similar conversion
of 6 to 1 (Scheme 2). A modest preference for the syn
product in one case relative to a slight preference for the
anti product in the other represents a very modest shift
in the relative free energies of the respective transition
states.
We attempted to convert the pyrrolidinone 15a , which
has the incorrect stereochemistry at C.3, to its epimer
(13) (a) Davies, S. G.; Walters, I. A. S. J . Chem. Soc., Perkin Trans.
1 1994, 1129-1139. (b) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J .;
Walters, I. A. S. Tetrahedron: Asymmetry 1994, 5, 35-36. (c) Chip-
pindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.; Smethurst,
C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Tetrahedron 2003, 59, 3253-
3265.
(12) Although better diastereoselectivity is obtained in the Michael
reaction when tert-butyl crotonate is used as opposed to isobutyl
crotonate, the high cost and relative unavailability of tert-butyl
crotonate precluded its development as a reagent for the Michael
addition for large-scale synthesis.
9614 J . Org. Chem., Vol. 68, No. 25, 2003

N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl}amine
SCHEME 5a
SCHEME 7a
a
Reagents and conditions: (a) KOt-Bu, THF; (b) saturated
NH4Cl.
SCHEME 6a
a
Reagents and conditions: (a) O3, H2O, 0 °C; (b) NaBH4; (c)
CH2Cl2 extraction (70-85% for a, b, and c); (d) MsCl, Et3N, THF;
(e) BnNH2, 50-60 °C (75-90% for e and d); (f) toluene, reflux, 3
h (90-95%); (g) LAH, THF, reflux; (h) Pd(OH)2, H2, MeOH (75-
90% for g and h).
The â-lactam 17 was converted to the amino â-lactam
19 by a two-step procedure. Ozonolytic cleavage of the
double bond followed by reduction of the resulting meth-
oxyhydroperoxide with dimethyl sulfide produced an
aldehyde. This unstable aldehyde was not isolated, but
was converted to the amino â-lactam by a reductive
amination. A higher yielding method for the preparation
of this amino â-lactam involves reductive workup of the
ozonolysis product with NaBH4 to yield alcohol 18. The
initial ozonolyses were done in CH2Cl2 or in CH2Cl2:
MeOH solutions; however, large-scale (>1 kg) reactions
required a safer system in which to run these O2-rich
reactions. The â-lactam 17 is soluble in water and since
water has been used successfully as an ozonolysis solvent,
we tried the ozonolysis in water. The reaction worked
cleanly to give an aldehyde, which was reduced in situ
with NaBH4, as shown in Scheme 7. Alcohol 18 was
activated as the mesylate, which was displaced with
benzylamine at 50-60 °C to yield a mixture of amino
â-lactam 19 and pyrrolidinone 20.
Complete conversion of amino â-lactam 19 to pyrroli-
dinone 20 was accomplished in toluene at 80-90 °C in
90-95% yield. No epimerization occurred under these
conditions. When this reaction was carried out under
basic conditions with LDA at -50 °C in THF, epimer-
ization occurred at the R-carbon. The transamidation
could, however, be carried out under acidic conditions
(AcOH, MeOH, 60 °C, 4 h) without epimerization.
Reduction of γ-lactam 20 with LAH in refluxing THF
occurred without epimerization to give the N-benzylpyr-
rolidine in 90% yield. Hydrogenolysis of the N-benzylpyr-
rolidine to diamine 1 occurred in 65-70% yield. Problems
with CO2 absorption onto the diamine probably caused
the lower yield for this hydrogenolysis.
a
Reagents and conditions: (a) Pd(OH)2, H2, EtOH; (b) LDA (2.2
equiv), THF, -40 °C; (c) allyl bromide (1.9 equiv).
with the correct configuration by equilibration with KOt-
Bu in THF followed by quenching with saturated am-
monium chloride. Unfortunately, the mixture from this
attempted epimerization contained a 5:2 ratio of pyrro-
lidinones in which the diastereomer 15a , with the incor-
rect stereochemistry at C.3, predominated. The poor
diastereoselectivities observed during this reaction se-
quence caused us to abandon this route.
We next attempted to improve the diastereoselectivity
of the allylation step through a variation of the chelation-
controlled alkylation of â-aminobutanoates developed by
Seebach and co-workers.3 Hydrogenolysis of 5c, as shown
in Scheme 6, yielded isobutyl (S)-3-(N-methyl)aminobu-
tyrate (16). Deprotonation of 16 can potentially lead to a
lithium-chelated dianion intermediate that can be ste-
reoselectively alkylated. When amine 16 was treated with
2 equiv of LDA and allyl bromide (1.9 equiv) was added
to the resulting anion, we observed the formation of a
single â-lactam 17. A search of the literature showed
several cases in which deprotonation of â-alkylamino
esters yielded â-lactams.14 Alkylation of the lithium-
chelated dianion can occur with subsequent closure to a
â-lactam, or the initially formed lithium amide can cyclize
to the â-lactam, which is subsequently deprotonated and
alkylated. The alkylation of the lithium-chelated dianion,
as judged by our experience with the alkylation of 8a and
8c, is not likely to be completely stereoselective, but once
the â-lactam has been formed, the diastereomer could be
epimerized to 17 under the basic reaction conditions.
With all of these possible reaction pathways, formation
of the desired diastereomer would be the expected
outcome. The stereocontrolled alkylation of â-lactams is
well precedented by numerous examples in the litera-
ture;15 however, this is the first direct formation and
alkylation of a â-lactam in one pot.
Con clu sion
We have produced a synthesis of N-methyl-N-{(1S)-1-
[(3R)-pyrrolidin-3-yl]ethyl}amine (1) in nine steps from
isobutyl crotonate in 38% overall yield. This synthesis
uses an asymmetric Michael reaction of a chiral lithium
amide, derived from (S)-(N-methyl)[N-(1-phenyl)ethyl]-
(14) Gennari, C.; Venturini, I.; Gislon, G.; Schimperna, G. Tetrahe-
dron Lett. 1987, 28, 227-230.
(15) Durst, T.; LeBelle, M. J . Can. J . Chem. 1972, 50, 3196-3201.
J . Org. Chem, Vol. 68, No. 25, 2003 9615

Fleck et al.
The solids were dissolved with CH2Cl2 (1.6 L). H2O (400 mL)
was added, and the pH was adjusted to 12 with 50% NaOH
(75 mL). The layers were separated, and the aqueous layer
was extracted again with CH2Cl2 (900 mL). The CH2Cl2
extractions were combined and distilled to give 0.142 g (80%)
of isobutyl (3S)-3-{methyl[(1S)-1-phenylethyl]amino}butanoate.
IR (liq) 2967 (s), 2939, 2312 (w), 1995 (w), 1948 (w), 1735 (s),
1453, 1369, 1302, 1293 (s), 1211, 1193 (s), 1079, 1009, 701 (s),
amine, to establish the stereochemistry at C.1′ of 1. The
stereochemistry at C.3 is set by using the stereochemistry
at C.1′ to control the outcome of the stereoselective
alkylation, which yields the key â-lactam intermediate
17. We have also presented our first synthesis of 1, which
relied on the stereoselective alkylation of a â-aminobu-
tanoate to establish the stereochemistry at C.3.
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.83 (6H, d, J ) 6.6 Hz),
0.90 (3H, d, J ) 6.6 Hz), 1.24 (3H, d, J ) 6.6 Hz), 1.81 (1H, 9
line m, J ) 6.6 Hz), 2.00 (3H, s), 2.18 (1H, dd, J ) 13.8, 7.5
Hz), 2.47 (1H, dd, J ) 13.8, 6.9 Hz), 3.49 (2H, m), 3.73 (1H,
dd, J ) 17.1, 6.6 Hz), 3.81 (1H, dd, J ) 17.1, 6.6 Hz), 7.09-
7.27 (5H, m); 13C NMR (75 MHz, CDCl3) δ 14.9 (q), 19.6 (q),
22.1 (q), 28.1 (d), 32.5 (t), 39.4 (t), 51.6 (d), 62.5 (d), 70.9 (d),
127.1 (d), 127.6 (d), 128.6 (d), 146.6 (s), 173.2 (s); HRMS (FAB)
calcd for C17H27NO2 + H1 278.2120, found 278.2120. Anal.
Calcd for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C,
73.56; H, 9.73; N, 5.21.
Exp er im en ta l Section
N-F or m yl-N-(S)-m eth ylben zyla m in e (4c). (S)-Methyl-
benzylamine (107 g, 0.88 mol) and ethyl formate (180 g, 2.4
mol) were heated to reflux (51 °C) for 18 h. THF (110 mL)
was added, and the solution was distilled to dryness. In the
1H and 13C NMR, the compound exists as a 90:10 mixture of
rotamers about the C-N bond of the acyl group. Only data
for the major isomer are listed. IR (liq) 3277 (b), 3031, 2976,
1996 (w), 1952 (w), 1661 (s), 1534, 1495, 1451, 1384, 1378,
1239, 762, 699 (s), 608, cm-1; H NMR (400 MHz, d6-DMSO)
1
Isobu tyl (3S)-3-(Meth yla m in o)bu ta n oa te (16). To a
hydrogenation vessel containing 5% Pd/C (50 g, 30 wt %) was
added isobutyl (3S)-3-{methyl[(1S)-1-phenylethyl]amino}-
butanoate (160 g, 0.61 mol) and 1.8 L of 2-propanol. Hydro-
genation at 40 psig at 50 °C was carried out for 11.5 h until
hydrogen uptake ceased. The slurry was filtered and rinsed
with 2-propanol (100 mL). Azeotropic vacuum distillation with
heptane (600 mL) gave 88 g (83%) of isobutyl (3S)-3-(methyl-
amino)butanoate. IR (liq) 2965 (s), 2895, 2876, 1996 (w), 1733
(s), 1472, 1380, 1370, 1304, 1294, 1249, 1196, 1170, 1158 (s),
δ 1.36 (3H, d, J ) 7.0 Hz), 5.00 (1H, quintet, J ) 7.5 Hz), 7.20-
7.26 (3H, m), 7.30-7.35 (2H, m), 8.04 (1H, s), 8.53 (1H, d, J )
7.1 Hz); 13C NMR (125 MHz) δ 23.3, 47.4, 126.8, 127.6, 129.1,
145.0, 160.9; MS (FAB) m/z (rel intensity) 150 (MH+, 99), 303
(4), 300 (10), 299 (47), 253 (5), 151 (11), 150 (99), 148 (5), 106
(9), 105 (68), 46 (10); HRMS (FAB) calcd for C9H11NO + H1
150.0919, found 150.0924. Anal. Calcd for C9H11NO: C, 72.46;
H, 7.43; N, 9.39. Found: C, 72.01; H, 7.46; N, 9.38.
Meth yl (S)-Meth ylben zyla m in e (4b). To THF (400 mL)
was added a slurry of 10 wt % of LiAlH4 (340 g, 0.90 mol),
and the slurry was cooled to -20 °C. To the diluted LiAlH4
slurry was added a solution of N-formyl-N-(S)-methylbenzyl-
amine (121 g, 0.81 mol) dissolved in THF (220 mL) over 30
min. The solution was then heated to 63 °C for 8 h and then
cooled to 8 °C. NaOH (50%, 750 g) was added over 2 h as the
reaction mixture was cooled, using a CH3CN/dry ice bath.
Citric acid (50%, 880 g) was added to a pH of 10 followed by
H2O (500 mL). The product was extracted with EtOAc (2 ×
800 mL). The combined EtOAc layers were washed with 2%
Na2CO3 (400 mL), and the Na2CO3 solution was back extracted
with EtOAc (600 mL). The combined EtOAc extracts were
distilled and azeotroped with THF (750 mL) followed by
toluene (400 mL) to remove water to give 90 g of methyl (S)-
methylbenzylamine (83% yield from (S)-methylbenzylamine).
IR (liq) 3025, 2970, 2932, 2869 (b), 2845, 2789, 2332 (w), 1996
1
1006, cm-1; H NMR (300 MHz, CDCl3) δ 0.93 (6H, d, J ) 6
Hz), 1.51 (3H, d, J ) 6 Hz), 1.94 (1H, septet, J ) 6.5 Hz), 2.70
(3H, s), 2.77 (1H, dd, J ) 18, 9 Hz), 3.11 (1H, dd, J ) 18, 6
Hz), 3.57 (1H, m), 3.92 (2H, m), 8.3-9.1 (1H, br s); 13C NMR
(75 MHz, CDCl3) δ 16.6 (q), 19.1 (q), 27.6 (d), 30.3 (q), 37.5 (t),
52.2 (d), 71.4 (t), 169.8 (s); MS (EI) m/z (rel intensity) 173 (M+,
1), 158 (5), 102 (7), 59 (3), 58 (99), 57 (9), 56 (8), 43 (4), 42 (7),
41 (10), 39 (5); HRMS (EI) calcd for C9H19NO2 173.1416, found
173.1419. Anal. Calcd for C9H19NO2: C, 62.39; H, 11.05; N,
8.08. Found: C, 62.35; H, 11.24; N, 8.03. [R]25 -1 (c 0.75).
D
(3S,4S)-3-Allyl-1,4-d im eth yla zetid in -2-on e (17). To a
freshly prepared LDA solution (122 g of diisopropylamine, 1230
mL of THF, and 514 g of 15% n-BuLi) at -75 °C was added a
solution of isobutyl (3S)-3-(methylamino)butanoate (89 g, 0.51
mol) in THF (500 mL) over 2 h. The solution was stirred for 1
h and a solution of allyl bromide (125 g, 1.04 mol) in THF (450
mL) was added at -78 °C over 2 h. The reaction was quenched
into a 0 °C aqueous NH4Cl solution (181 g in 600 mL of H2O).
The pH was adjusted to 5 with 37% HCl (190 g). The organic
layer was separated, and the aqueous layer was extracted with
EtOAc (600 mL). The combined organic extracts were distilled
and purified by plug chromatography, using 50:50 EtOAc:
heptane, to give 60 g (83%) of (3S,4S)-3-allyl-1,4-dimethylaze-
(w), 1948 (w), 1493, 1476, 1450, 1137, 761 (s), 701 (s), cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.25 (3H, d, J ) 6.6 Hz), 1.44
(1H, br s), 2.21 (3H, s), 3.54 (1H, q, J ) 6.6 Hz), 7.10-7.26
(5H, m); 13C NMR (100 MHz, CDCl3) δ 24.2 (q), 34.8 (q), 60.5
(d), 126.8 (d), 127.1 (d), 128.7 (d), 145.6 (s); HRMS (FAB) calcd
for C9H13N + H1 136.1126, found 136.1110. Anal. Calcd for
C9H13N: C, 79.95; H, 9.69; N, 10.36. Found: C, 79.70; H, 9.46;
N, 10.56.
1
tidin-2-one. H NMR (500 MHz, CDCl3) δ 1.29 (3H, d, J ) 6
Hz), 2.33 (1H, m), 2.52 (1H, m), 2.75 (3H, s), 2.76 (1H, br s),
3.29 (1H, dq, J ) 6, 2 Hz), 5.05 (1H, dt, J ) 10, 3 Hz), 5.08
(1H, dt, J ) 15.5, 3 Hz), 5.81 (1H, dddd, J ) 15, 11, 7, 7 Hz);
13C NMR (125 MHz, CDCl3) δ 17.2 (q), 25.8 (q), 32.2 (t), 54.7
(d), 56.4 (d), 116.6 (t), 134.6 (d), 169.1 (s).
Isob u t yl (3S)-3-{Met h yl[(1S)-1-p h en ylet h yl]a m in o}-
bu ta n oa te (5c). To a THF (2.6 L) solution of methyl (S)-
methylbenzylamine (155 g, 1.15 mol) at -30 °C was added 24
wt % of n-BuLi (319 g, 1.19 mol) over 50 min. The solution
was stirred for 30 min and cooled to -75 °C. A solution of
isobutyl crotonate (155 g, 1.09 mol) in THF (680 mL) was
added over 4 h and the solution was stirred an additional 30
min. The reaction was quenched at -70 °C over 1 h with a 14
wt % aqueous solution of NH4Cl (245 g) to a pH of 2.4. The
solution was warmed to 20 °C and diluted with H2O (225 mL).
The aqueous layer was separated and washed with EtOAc (1.4
L). The organic extracts were combined and the solution was
distilled to a volume of 300 mL. The resulting slurry was
filtered and washed with EtOAc (300 mL). The filtrate was
distilled to a volume of 350 mL and MeOH (600 mL) was
added. The solution was cooled to -5 °C and 37% HCl (116 g,
1.14 mol) was added over 25 min. MTBE (3 L) was added and
the mixture was cooled to -20 °C and stirred for 2 h. The
resulting solids were filtered and rinsed with MTBE (220 mL).
(3S ,4S )-3-(2-H yd r oxye t h yl)-1,4-d im e t h yla ze t id in -2-
on e (18). A solution of (3S,4S)-3-allyl-1,4-dimethylazetidin-
2-one (71 g, 0.36 mol) in H2O (180 mL) was cooled to 0 °C.
Ozonolysis was continued until the reaction was complete by
GC. NaBH4 (16 g, 0.42 mol) was added in 1-2 g shots. NaCl
(100 g) was added and the product was extracted with CH2-
Cl2 (9 × 600 mL). The combined organic extracts were distilled
and purified by plug chromatography, using 50:50 EtOAc:
heptane, to give 35.6 g (49%) of (3S,4S)-3-(2-hydroxyethyl)-
1,4-dimethylazetidin-2-one. IR (liq) 3415 (b), 2962, 2929, 2879
(b), 2465 (w), 2155 (w), 1996 (w), 1731 (s), 1428, 1398, 1381,
1
1363, 1347, 1052, 1001, cm-1; H NMR (400 MHz, CDCl3) δ
1.31 (3H, d, J ) 6.0 Hz), 1.88 (2H, dt, J ) 6.0, 3.0 Hz), 2.73
(1H, t, J ) 7.6 Hz), 2.75 (3H, s), 3.33 (1H, dq, J ) 6.0, 3.0 Hz),
9616 J . Org. Chem., Vol. 68, No. 25, 2003

N-Methyl-N-{(1S)-1-[(3R)-pyrrolidin-3-yl]ethyl}amine
3.71 (2H, t, J ) 5.8 Hz); 13C NMR (100 MHz, CDCl3) 17.4 (q),
26.4 (q), 31.6 (d), 55.6 (t), 56.0 (t), 61.3 (d), 170.6 (s); HRMS
(FAB) calcd for C7H13NO2 + H1 144.1024, found 144.1014.
(3S)-1-Ben zyl-3-[(1S)-1-(m eth ylam in o)eth yl]pyr r olidin -
2-on e (20). To a solution of (3S,4S)-3-(2-hydroxyethyl)-1,4-
dimethylazetidin-2-one (35 g, 0.24 mol) in CH2Cl2 (640 mL)
at 0 °C was added Et3N (62 g, 0.61 mol) followed by a solution
of MsCl (30 g, 0.26 mol) in CH2Cl2 (45 mL) over 30 min. The
reaction was quenched with a dilute aqueous HCl solution (76
g of 37% HCl and 300 mL of H2O). The aqueous phase was
separated and extracted with CH2Cl2 (400 mL). The combined
CH2Cl2 extracts were again washed with a dilute aqueous HCl
solution (38 g of 37% HCl and 300 mL of H2O). The aqueous
phase was back extracted with CH2Cl2 (400 mL). The combined
CH2Cl2 extracts were vacuum distilled. THF (400 mL) was
added and the resulting solution was again vacuum distilled.
THF (1.0 L) and benzylamine (65 g, 0.61 mol) were added, and
the solution was heated to 60 °C for 64 h. The reaction mixture
was cooled to 0 °C, filtered, and distilled to a volume of 200
mL. A pure sample was obtained by chromatography. 1H NMR
(500 MHz, CDCl3) δ 0.98 (3H, d, J ) 6.5 Hz), 1.71 (1H, m),
1.97 (1H, m), 2.37 (3H, s), 2.54 (1H, q, J ) 8.5 Hz), 2.85 (1H,
quintet, J ) 6.5 Hz), 2.99 (1H, br s), 3.08-3.11 (2H, m), 4.32
(1H, d, J ) 14.7 Hz), 4.40 (1H, d, J ) 14.7 Hz), 7.13-7.25
(5H, m); 13C NMR (125 MHz, CDCl3) δ 16.2 (q), 20.7 (t), 33.5
(q), 44.7 (t), 45.3 (d), 46.5 (t), 56.3 (d), 127.4 (d), 127.9 (d), 128.5
(d), 135.3 (s), 175.5 (s).
N-{(1S)-1-[(3R)-1-Ben zylp yr r olid in -3-yl]eth yl}-N-m eth -
yla m in e (10). The crude (3S)-1-benzyl-3-[(1S)-1-(methylami-
no)ethyl]pyrrolidin-2-one was dissolved in THF (100 mL) and
added over 2 h to a 70 °C slurry of 10 wt % of LiAlH4 (140 g,
0.36 mol) in THF (600 mL). After the solution was stirred for
64 h, the product slurry was cooled to 10 °C and quenched
with 50% NaOH (75 g). Citric acid (50%, 65 g) was added to a
pH of 11. The reaction was diluted with H2O (500 mL) and
the phases were separated. The aqueous phase was extracted
with THF (400 mL). The combined THF extracts were vacuum
distilled. Toluene (400 mL) was added and the resulting
solution was vacuum distilled. H2O (500 mL), NaCl (50 g), and
EtOAc (150 mL) were added, and the EtOAc layer was
separated. The aqueous layer was extracted with THF (1 ×
200 mL, 1 × 400 mL). The organic extracts were combined
and vacuum distilled. Toluene (400 mL) was added and the
resulting solution was vacuum distilled to give crude N-{(1S)-
1-[(3R)-1-benzylpyrrolidin-3-yl]ethyl}-N-methylamine. A pure
sample was obtained by chromatography. IR 2962, 2787, 1453,
1375, 1151, 738, 698 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.02
(3H, d, J ) 6.3 Hz), 1.51 (1H, m), 1.88 (1H, m), 2.14 (1H, m),
2.25 (1H, dd, J ) 8.8, 7.6 Hz), 2.37 (3H, s), 2.35-2.47 (2H, m),
2.66 (1H, br q, J ) 7.7 Hz), 2.76 (1H, dd, J ) 8.5, 8.1 Hz), 3.39
(1H, br s), 3.58 (1H, d, J ) 12.9 Hz), 3.60 (1H, d, J ) 12.9 Hz),
7.15-7.32 (5H, m); 13C NMR (75 MHz, CDCl3) δ 17.5 (q), 27.6
(t), 34.8 (q), 43.7 (d), 54.1 (t), 57.7 (t), 58.9 (d), 60.7 (t), 77.0
(CDCl3), 126.8 (s), 128.1 (s), 128.7 (s), 139.1 (s); MS (EI, 70
eV) m/z (rel intensity) 218 (M+, 3), 203 (2), 187 (48), 172 (36),
91 (100), 58 (59); [R]D +2° (c 1.02, MeOH).
N-Meth yl-N-{(1S)-1-[(3R)-p yr r olid in -3-yl]eth yl}a m in e
(1). To a hydrogenation vessel was added 20 wt % of Pd(OH)2
(2 g, 8 wt %), crude N-{(1S)-1-[(3R)-1-benzylpyrrolidin-3-yl]-
ethyl}-N-methylamine, and MeOH (400 mL). Hydrogenation
at 20 °C was performed for 64 h with the addition of three
more aliquots of 2, 8, and 8 g of Pd(OH)2 until the reaction
was complete. The slurry was filtered, rinsed with MeOH (50
mL), and distilled to an oil. The oil was distilled at very high
vacuum to give 13.9 g (44% overall yield from (3S,4S)-3-(2-
hydroxyethyl)-1,4-dimethylazetidin-2-one). IR (liq) 3290 (s, b),
2965 (s), 2871 (s), 2793 (s), 1996 (w), 1546, 1477, 1446 (s), 1418
(s), 1372, 1329, 1157, 889, 814, 721, cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.06 (3H, d, J ) 6.3 Hz), 1.39 (1H, dddd, J ) 12.3,
8.1, 8.1, 8.1 Hz), 1.60 (2H, br s), 1.86 (1H, m), 2.00 (1H, 6 line
m, J ) 8.1 Hz), 2.40 (3H, br s), 2.42 (1H, m), 2.61 (1H, dd,
J ) 10.8, 7.8 Hz), 2.87-2.96 (2H, m), 3.11 (1H, dd, J ) 10.8,
7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 17.8 (q), 29.4 (t), 33.7
(q), 45.9 (d), 46.8 (t), 50.5 (t), 58.5 (d); MS (EI) m/z (rel
intensity) 128 (M+, 1), 98 (8), 97 (46), 84 (10), 82 (33), 71 (9),
70 (9), 69 (7), 68 (9), 58 (99), 56 (8); HRMS (FAB) calcd for
C7H16N2 + H1 129.1392, found 129.1395.
Ack n ow led gm en t. We are grateful to the Analytical
Chemistry Department of Pfizer for acquiring the IR,
UV, HRMS, and combustion analysis data. We thank
Dr. J ed F. Fisher for assistance with the preparation of
this manuscript.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
1
5a , 5b, 8a , 8c, 6a , 6b, 6c, 9, 10, 10a , and 1b; H-1H COSY,
HMQC, and HMBC NMR spectra of 1b; general information
of the experimental section and experimental procedures for
5a , 5b, 8a , 7b, 8c, 8b, 6a , 6c, 6b, 9, 10, 10a , and 1b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0349633
J . Org. Chem, Vol. 68, No. 25, 2003 9617